Black Box For Avandia and Actos:
Yet Another Example of Pharma Influence Over FDA

August 14, 2007

The FDA and GlaxoSmithKline (GSK) both just announced that negotiations between the drug companies and FDA regarding the new, strengthened warnings for the diabetes drugs including Avandia and Actos (rosiglitazone and pioglitazone) are complete. The result: a black box warning that these drugs

- "cause or exacerbate congestive heart failure in some patients"

- are "not recommended in patients with symptomatic heart failure"

- are "contraindicated" for patients with NYHA Class III or IV heart failure.

FDA’s announcement of this label change and the fact that it applies to both Avandia and Actos illustrates the improper influence of a drug company, in this case GSK, over the FDA.

First of all, one expects the drug company to put the best spin possible on its announcement that its number two top-selling drug has a safety risk. Predictably, GSK’s press release characterizes this label change as addressing a "well known and well characterized" risk. GSK weaves language throughout the press release to give the impression it has always warned about this risk. No doubt, GSK will use this argument in litigation to avoid liability for its alleged failure to warn by claiming that this heart risk is something which doctors and patients have always known (even though it continues to publicly deny this risk exists).

More disturbing, however, is the similarity between GSK’s press release and FDA’s announcement of this label change. Obviously, FDA itself needs to put a spin on this in order to downplay its own failure to follow up on its own safety officers’ recommendations that this risk be studied as a condition to approval itself.

Similar to GSK’s "well-known risk" spin, FDA’s statement includes a quote from Dr. Steven Galson, director of FDA’s Center for Drug Evaluation and Research (CDER -- the arm of the FDA recognized as repeatedly vetoing FDA’s safety officers’ recommendations). Dr. Galson’s quote begins with a self-serving statement that the FDA "carefully monitor(s)" safety information through its postmarketing surveillance program (the same program the Institute of Medicine, after its independent evaluation only a year ago, recommended be overhauled in order to make it effective). Then the CDER’s Dr. Galson parrots GSKs’ spin by characterizing the black box not as a new warning, but as a way to address doctors’ failure to properly monitor their patients for these "known" risks. Ironic when the debate at both the congressional hearing on June 6, 2007 and the FDA’s advisory committee hearing on July 30, 2007 was about whether this risk even exists.

Most disturbing, and most dangerous, is the fact that these negotiations between GlaxoSmithKline and the FDA’s CDER officials have resulted in, once again, a label change that contradicts the recommendations of FDA’s own safety officers, including not just Dr. David Graham (the well-known "whistle-blower") but also Dr. Gerald Dal Pan (the Director of FDA’s Office of Drug Safety). At the advisory committee hearing, Dr. Graham presented data to support the FDA’s Drug Safety Office’s conclusions: Avandia does "increase cardiovascular risk compared to its non-use"; Actos "does not increase cardiovascular risk"; "Avandia has no unique short-term benefits related to glycemic control"; Avandia "has no demonstrated long-term health benefits related to cardiovascular disease, diabetic retinopathy, nephropathy, or neuropathy."

FDA’s Drug Safety Office recommended that Avandia be taken off the market, in part because alternative, safer treatments including Actos are available. The risks of taking Avandia are potentially fatal to patients; the risk of taking Avandia off the market is fatal to GSK’s enormous Avandia-related profits.

The advisory committee rejected the recommendation to take Avandia off the market, what it did not determine is what the black box would look like and, more importantly, whether it would be "class-wide." The negotiations between GSK and FDA apparently determined that, in contradiction to what FDA’s evidence showed, a class warning would be instituted.

According to Baum Hedlund:

"GSK avoided the quick death of Avandia profits with the advisory committee’s rejection of the recall; but GSK’s private, post-public hearing negotiations with FDA’s CDER officials successfully avoided the slow death Avandia would have suffered if FDA required a stronger warning for Avandia than its primary competitor, Actos. This type of negotiated result is driven by drug company interests, not by patient safety. The line between the FDA and Pharma just got fuzzier."

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